Contents:

Objectives:

Objectives To discuss the epidemiology, clinical manifestations, approach to diagnosis and management of pituitary diseases To discuss the mechanism of action, adverse effects and clinical use of drugs for pituitary diseases

PITUITARY GLAND (THE HYPOPHYSIS):

PITUITARY GLAND (THE HYPOPHYSIS) The pituitary is located at the base of the brain, in a small depression of the sphenoid bone (sella turcica). Purpose: control the activity of many other endocrine glands. “ Master gland” Has two lobes, the anterior & posterior lobes.

ANATOMY:

ANATOMY Anterior lobe ( adenohypophysis ): glandular tissue, accounts for 75% of total weight. Hormones in this lobe are controlled by regulating hormones from the hypothalmus (stimulate or inhibit) Posterior ( neurohypophysis ) : nerve tissue & contains axons that originate in the hypothalmus . Therefore this lobe does not produce hormones but stores those produced by the neurosecretory cells in the hypothalmus . Release of hormones is triggered by receptors in the hypothalmus .

GROWTH HORMONE…:

GROWTH HORMONE… The growth-promoting effects of GH are largely mediated by insulin-like growth factors (IGFs) also known as somatomedins . GH stimulates the formation of insulin-like growth factor-1 ( IGF-1 ) in the liver as well as in other peripheral tissues.

GROWTH HORMONE…:

GROWTH HORMONE… Growth hormone (GH) is a single-chain 191– amino acid polypeptide with a molecular size of 22 kilodaltons ( kDa ) It is synthesized in and released from somatotrope cells, which constitute the most numerous cell type in the anterior pituitary

GROWTH HORMONE…:

GROWTH HORMONE… GH exerts a broad spectrum of eﬀects , resulting in growth promotion and the regulation of carbohydrate, protein, lipid, and mineral metabolism These are mediated by direct eﬀects on peripheral tissues and indirect eﬀects on the liver and other tissues through the generation of insulin-like growth factor-1 (IGF-1) Nearly 80% of circulating IGF-1 is of hepatic origin

GROWTH HORMONE…:

GROWTH HORMONE… There are two types of insulin-like growth factors: IGF-1 and IGF-2 IGF-1 regulates growth to some extent before, and largely after, birth. In contrast, IGF-2 is thought to primarily regulate growth in utero

GROWTH HORMONE…:

GROWTH HORMONE… The synthesis and secretion of GH are regulated primarily through the actions of hypothalamic neuropeptides that integrate hormonal, metabolic, and neurogenic signals. The half-life of GH in serum is 20 to 25 minutes ; the secretion rate in young adult men is approximately 600 mg/d, and it is approximately 900 mg/d in young adult women

PULSATILITY OF GROWTH HORMONE SECRETION:

PULSATILITY OF GROWTH HORMONE SECRETION GH secretion occurs in a pulsatile manner in humans and in all other species examined, with from 8 to 12 pulses occurring in a 24-hour period

AGE AND GH:

AGE AND GH GH secretion is maximal during puberty and through the third decade, after which it declines progressively with age. A similar decline in slow wave sleep occurs during this same period, suggesting at least partial entrainment of GH with sleep. Sleep-associated GH secretion can be inhibited by cholinergic muscarinic receptor blockade

GROWTH HORMONE EXCESS:

GROWTH HORMONE EXCESS

GH EXCESS:

GH EXCESS Acromegaly is a pathologic condition characterized by excessive production of GH and insulin-like growth factor 1 (IGF-1). This is a rare disorder that affects approximately 50 to 70 adults per million. Gigantism , which is even more rare than acromegaly , is the excess secretion of GH prior to epiphyseal closure in children.

GH EXCESS…:

GH EXCESS… Patients diagnosed with acromegaly are reported to have a twofold to threefold increase in mortality , usually related to cardiovascular , respiratory , or neoplastic disease . Most patients are middle-aged at the time of diagnosis, and this disorder does not appear to affect one gender to a greater extent than the other .

GH EXCESS…:

GH EXCESS… The most common cause of excess GH secretion in acromegaly is a GH-secreting pituitary adenoma , accounting for approximately 98% of all cases. Rarely, caused by Ectopic GH-secreting adenomas , GH cell hyperplasia , or excess GHRH secretion , …

PATHOGENESIS OF ACROMEGALY:

PATHOGENESIS OF ACROMEGALY Hypersecretion of GH or GH-releasing hormone (GHRH) can lead to acromegaly Pituitary GH-secreting adenomas are responsible for 98% of acromegaly and almost exclusively are benign

CLINICAL PRESENTATION OF ACROMEGALY:

CLINICAL PRESENTATION OF ACROMEGALY General The patient will experience slow development of soft-tissue overgrowth affecting many body systems. Signs and symptoms may gradually progress over 7 to 10 years.

CLINICAL PRESENTATION OF ACROMEGALY…:

CLINICAL PRESENTATION OF ACROMEGALY… Symptoms The patient may complain of symptoms related to local effects of the growth hormone (GH)-secreting tumor , such as headache and visual disturbances . Other symptoms related to elevated GH and insulin-like growth factor-1 (IGF-1) concentrations include excessive sweating, neuropathies, joint pain, and paresthesias .

CLINICAL PRESENTATION OF ACROMEGALY…:

CLINICAL PRESENTATION OF ACROMEGALY… Laboratory tests The patient’s GH concentration will be >1 mcg/L following an oral glucose tolerance test (OGTT) and IGF-1 serum concentrations will be elevated. Glucose intolerance may be present in up to 50% of patients.

CLINICAL PRESENTATION OF ACROMEGALY…:

CLINICAL PRESENTATION OF ACROMEGALY… Additional clinical sequelae Cardiovascular diseases such as hypertension, coronary heart disease, cardiomyopathy, and left ventricular hypertrophy are common in patients with acromegaly. Osteoarthritis and joint damage develops in up to 90% of acromegalic patients. Respiratory disorders and sleep apnea occur in up to 60% of acromegalic patients.

CLINICAL PRESENTATION OF ACROMEGALY…:

CLINICAL PRESENTATION OF ACROMEGALY… Type 2 diabetes develops in approximately 25% of acromegalic patients. Patients with acromegaly may have an increased risk for development of esophageal, colon, and stomach cancer.

DIAGNOSIS:

DIAGNOSIS History & physical exam Investigation includes: GH analysis (glucose tolerance) Normally GH concentarion falls with oral glucose; in acromegaly it does not. Prolactin levels as well as other pituitary function tests MRI or CT & visual field tests to determine size and position of the adenoma. Bone scan

TREATMENT:

DESIRED OUTCOME:

DESIRED OUTCOME The goals of treatment for Pituitary Gland Disorders are to limit morbidity and mortality and return the patient to a normal functional state by removing the source of either Increased or decreased state of the gland without causing any further pituitary complications.

COMPLICATIONS OF RADIATION THERAPY:

PHARMACOLOGIC THERAPY:

PHARMACOLOGIC THERAPY Drug therapy should be considered for acromegalic patients in whom surgery and irradiation are contraindicated , when rapid control of symptoms is indicated, or when other treatments have failed to normalize GH and IGF-1 concentrations. Pharmacologic treatment options include dopamine agonists , somatostatin analogs , and the GH receptor antagonist pegvisomant .

GROWTH HORMONE RECEPTOR ANTAGONIST:

GROWTH HORMONE RECEPTOR ANTAGONIST Pegvisomant , a GH receptor antagonist, is highly effective in normalizing IGF-1 concentrations in up to 97% of patients. However, additional long-term data are needed to establish the safety and efficacy of pegvisomant in the management of acromegaly

EVALUATION OF THERAPEUTIC OUTCOMES:

EVALUATION OF THERAPEUTIC OUTCOMES Close monitoring of Pituitary Insufficiency and Deficits in Visual Acuity during GAMMA KNIFE therapy GH, IGF-1 and glucose intolerance test of blood should be monitored with all drug therapy

CONCLUSIONS:

CONCLUSIONS Acromegaly is a chronic debilitating disease characterized by excess GH secretion most commonly caused by a GH-secreting pituitary adenoma. Transsphenoidal surgical resection of the adenoma is the current treatment of choice for most patients with acromegaly . Drug therapy options for acromegaly include dopamine agonists , the somatostatin analog octreotide , and pegvisomant .

Growth Hormone Deficiency (GHD):

Growth Hormone Deficiency (GHD)

GHD~ Short Stature :

GHD~ Short Stature Short stature is a condition that is commonly defined by a physical height that is more than two standard deviations below the population mean and lower than the third percentile for height in a specific age group. A true lack of GH is among the least common causes and is known as growth hormone deficient (GHD) short stature.

Short Stature:

Short Stature Absolute GH deficiency is a congenital disorder that can result from various genetic abnormalities, such as: GHRH deficiency , GH gene deletion , and developmental disorders including pituitary aplasia or hypoplasia .

Short Stature:

Short Stature GH insufficiency is an acquired condition that can result secondary to: hypothalamic or pituitary tumors , cranial irradiation, head trauma, pituitary infarction, and various types of CNS infections.

Clinical Presentation of Short Stature:

Clinical Presentation of Short Stature General The patient will have a physical height that is greater than two standard deviations below the population mean for a given age and gender. Signs The patient will present with reduced growth velocity and delayed skeletal maturation.

Clinical Presentation of Short Stature:

Clinical Presentation of Short Stature Children with growth hormone (GH)-deficient or GH-insufficient short stature may also present with central obesity, prominence of the forehead, and immaturity of the face.

Clinical Presentation of Short Stature:

Clinical Presentation of Short Stature Laboratory tests The patient will exhibit a peak GH concentration <10 mcg/L following a GH provocation test. Reduced insulin-like growth factor-1 and insulin-like growth factor-1 binding protein-3 concentrations may be present. Because GH deficiency may be accompanied by loss of other pituitary hormones, hypoglycemia and hypothyroidism may be noted.

TREATMENT (recombinant GH):

TREATMENT ( recombinant GH) Replacement with recombinant GH is considered the mainstay of therapy for patients with GHD short stature, but its use for treatment of non-GHD short stature remains controversial, albeit such treatment is FDA approved . Recombinant GH has proven to be safe for use in children and is associated with few adverse effects.

TREATMENT (synthetic GHRH ):

TREATMENT (synthetic GHRH ) A synthetic GHRH product known as sermorelin ( Geref ) currently is FDA approved for the treatment of idiopathic GH deficiency( non- GHD short stature) in children. Sermorelin [GH-RH(1–29)-NH2] is composed of 29 amino acid residues that are identical to the amino-terminal segment of human GHRH.

TREATMENT…:

TREATMENT… GH regimens can be particularly demanding and inconvenient for pediatric patients because they must be administered by subcutaneous injection. Knowledge of the long term benefits and risks is critical to the development of rational, cost-effective treatments for patients with short stature

EVALUATION OF THERAPEUTIC OUTCOMES OF GHD:

EVALUATION OF THERAPEUTIC OUTCOMES OF GHD Appropriate monitoring of therapy for GHD and non-GHD short stature includes regular assessments of: height, weight, growth velocity, serum alkaline phosphatase, and bone age every 6 to 12 months.

EVALUATION OF THERAPEUTIC OUTCOMES OF GHD:

EVALUATION OF THERAPEUTIC OUTCOMES OF GHD Additional laboratory tests to monitor for potential adverse effects include serum glucose concentration and thyroid function. The dose of GH will periodically need to be increased as weight increases in growing children.

PowerPoint Presentation:

PROLACTIN

PHYSIOLOGIC EFFECTS:

PHYSIOLOGIC EFFECTS Prolactin is secreted in a pulsatile fashion by the lactotroph cells of the anterior pituitary, with the highest peak concentrations observed during sleep. The secretion of prolactin is regulated primarily by tonic hypothalamic inhibitory effects of dopamine . During pregnancy, prolactin serum concentrations rise substantially above normal.

HYPERPROLACTINEMIA:

HYPERPROLACTINEMIA Hyperprolactinemia is a state of persistent serum prolactin elevation. Prolactin concentrations >20 mcg/L observed on multiple occasions are generally considered indicative of hyperprolactinemia . Hyperprolactinemia usually affects women of reproductive age. The incidence of hyperprolactinemia in the general population is reported to be <1%.

aetiologies:

aetiologies The most common causes are benign prolactin -secreting pituitary tumors , known as prolactinomas , and various medications . Prolactinomas are classified according to size. Prolactin -secreting microadenomas are <10mm in diameter and often do not increase in size.

Aetiologies…:

Aetiologies… In contrast, macroadenomas are tumors with a diameter >10 mm that continue to grow and can cause invasion of surrounding tissues. In the presence of a prolactinoma , prolactin serum concentrations may remain normal or may be markedly elevated to thousands of micrograms per litre.

Aetiologies…:

Aetiologies… Any pharmacologic agent that antagonizes dopamine or increases the release of prolactin can induce hyperprolactinemia . Serotonin is a strong stimulator of prolactin secretion, and selective serotonin reuptake inhibitors ( SSRIs ) such as fluoxetine , paroxetine , sertraline , and fluvoxamine are the medications most frequently associated with hyperprolactinemia

Clinical Presentation of Hyperprolactinemia:

Clinical Presentation of Hyperprolactinemia General Hyperprolactinemia most commonly affects women and is very rare in men. Signs and symptoms The patient may complain of symptoms related to local effects of the prolactin secreting tumor , such as headache and visual disturbances , that result from tumor compression of the optic chiasm . •

Clinical Presentation of Hyperprolactinemia:

Clinical Presentation of Hyperprolactinemia:

Clinical Presentation of Hyperprolactinemia Additional clinical sequelae Prolonged suppression of estrogen in premenopausal women with hyperprolactinemia leads to decreases in bone mineral density and significant risk for development of osteoporosis . Risk for ischemic heart disease may be increased with untreated hyperprolactinemia .

The Goal of Therapy:

The Goal of Therapy The goal of therapy is to normalize prolactin serum concentrations reestablish gonadotropin secretion to restore fertility and reduce the risk of osteoporosis . In patients with asymptomatic elevations in serum prolactin , observation and close followup are appropriate.

The Goal of Therapy:

The Goal of Therapy Treatment goals are more aggressive in patients with prolactin secreting macroadenomas because these tumors are larger and can cause invasion of local tissues with significant visual defects. Therefore, in addition to normalizing prolactin concentrations, tumor shrinkage and correction of visual defects are primary goals of treatment

TREATMENT:

TREATMENT Medical therapy with dopamine agonists usually is more effective than transsphenoidal surgery (TSS) for both types of pituitary prolactinomas Postsurgical cure rates differ depending on tumor type and expertise of the neurosurgeon. Long-term cure rates are reported to be approximately 60% for microprolactinomas and only 25% for macroprolactinomas .

TREATMENT…:

TREATMENT… TSS is reserved for patients who are refractory to or cannot tolerate therapy with dopamine agonists and for patients with very large tumors that cause severe compression of adjacent tissues. Radiation therapy may require several years for effective tumor shrinkage and reduction in serum prolactin concentrations and usually is used only in conjunction with surgery

TREATMENT…:

TREATMENT… The treatment of hyperprolactinemia depends on the underlying cause of the abnormality. In cases of drug-induced hyperprolactinemia, discontinuation of the offending medication In cases for which an appropriate therapeutic alternative does not exist, medical therapy with dopamine agonists is warranted. Sex-steroid replacement also should be considered.

TREATMENT:

TREATMENT Treatment options for the management of prolactinomas include clinical observation, medical therapy with dopamine agonists, radiation therapy, and transsphenoidal surgical removal of the tumor .

PHARMACOLOGIC THERAPY OF HYPERPROLACTINEMIA:

PHARMACOLOGIC THERAPY OF HYPERPROLACTINEMIA

BROMOCRIPTINE:

BROMOCRIPTINE Bromocriptine was the first D2-receptor agonist to be used in the treatment of hyperprolactinemia and has been the mainstay of therapy for over 20 years. Decreases in serum prolactin concentrations occur within 2 hours of oral administration, with maximal suppression occurring after 8 hours and suppressive effects persisting for up to 24 hours.

BROMOCRIPTINE:

BROMOCRIPTINE Medical therapy with bromocriptine normalizes prolactin serum concentrations, restores gonadotropin production, and shrinks tumor size in approximately 90% of patients with microprolactinomas and 70% of patients with macroprolactinomas.

BROMOCRIPTINE:

BROMOCRIPTINE For the management of hyperprolactinemia, bromocriptine therapy typically is initiated at a dose of 1.25 to 2.5 mg once daily @ bedtime to minimize adverse effects. Usual therapeutic doses of bromocriptine range from 2.5 to 15 mg/day Bid/tid, although some patients may require doses as high as 40 mg/day.

BROMOCRIPTINE:

BROMOCRIPTINE The most common adverse effects associated with bromocriptine therapy include CNS symptoms such as headache, lightheadedness , dizziness, nervousness, and fatigue. Gastrointestinal effects such as nausea, abdominal pain, and diarrhea . (administered with food or Vaginal preparations)

PERGOLIDE:

PERGOLIDE Pergolide is a dopamine-receptor agonist with affinity for both D1- and D2-receptors. This agent is 10 to 1,000 times more potent than bromocriptine on a per milligram basis. Not FDA approved once-daily dosing withdrawn from the U.S. market because of cases of cardiac valvulopathy (similar to other ergot alkaloids)

CABERGOLINE…:

CABERGOLINE… Cabergoline is a long-acting dopamine agonist with high selectivity and affinity for dopamine D2-receptors approved for treatment of hyperprolactinemia and has been shown to effectively reduce serum prolactin concentrations in 80% to 90% of hyperprolactinemic patients. also effectively reduces tumor size in patients with both microprolactinomas and macroprolactinomas.

CABERGOLINE…:

CABERGOLINE… Cabergoline is commercially available as 0.5-mg oral tablets. The initial dose for treatment of hyperprolactinemia is 0.5 mg once weekly or in divided doses twice weekly. The usual dose is 1 to 2 mg weekly; however, doses as high as 4.5 mg weekly have been used. vaginal dosage to reduce the adverse effects associated with oral therapy

EVALUATION OF THERAPEUTIC OUTCOMES:

EVALUATION OF THERAPEUTIC OUTCOMES Prolactin serum concentrations should be monitored every 3 to 4 weeks after the initiation of any dopamine-agonist therapy to assess efficacy and appropriately titrate medication dosage symptoms such as headache, visual disturbances, menstrual cycles in women, and sexual function in men should be evaluated to assess clinical response to therapy

EVALUATION OF THERAPEUTIC OUTCOMES:

EVALUATION OF THERAPEUTIC OUTCOMES Once prolactin concentrations have normalized and clinical symptoms of hyperprolactinemia have resolved with therapy, prolactin serum concentrations should be monitored every 6 to 12 months. In patients receiving long-term treatment, the dose of the dopamine agonist can be gradually reduced or discontinued in some patients.

EVALUATION OF THERAPEUTIC OUTCOMES:

EVALUATION OF THERAPEUTIC OUTCOMES For patients with microprolactinomas who have normal serum prolactin concentrations and at least a 50% reduction in tumor size , medical therapy may be withdrawn every 2 to 5 years to assess if remission has been achieved . In the case of macroprolactinomas , the dose of the dopamine agonist can be gradually reduced in some cases, but complete drug discontinuation should be attempted only if careful monitoring for renewed tumor growth can be ensured

CONCLUSIONS:

CONCLUSIONS Hyperprolactinemia is a common disorder that can have a significant impact on fertility. Hyperprolactinemia is most commonly caused by the presence of prolactin-secreting pituitary tumors and various medications that antagonize dopamine or increase the secretion of prolactin.

CONCLUSIONS:

CONCLUSIONS Available treatment options for this disorder include medical therapy with dopamine agonists , radiation therapy , and transsphenoidal surgery . In most cases, medical therapy with dopamine agonists is considered the most effective treatment. Cabergoline has replaced bromocriptine because it appears to be better tolerated and more effective. during pregnancy , bromocriptine remains the preferred agent when fertility is the primary purpose for treatment.

PowerPoint Presentation:

Posterior Pituitary Disorders

Deficiency or Excess of ADH:

Posterior Lobe Disorders:

Posterior Lobe Disorders SIADH & diabetes insipidus are major disorders of the posterior pituitary……however Even if posterior lobe becomes damaged, hormonal deficiencies usually do not develop because……??

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Treatment of SIADH:

Treatment of SIADH Treat underlying cause Hypertonic or isotonic fluid Monitor for signs of fluid and electrolyte imbalance Monitor for neurological effects Monitor fluid in and out Followup Weight of the pt Restrict fluid intake Lithium inhibits action of ADH promote water excretion.

Diabetes Insipitus (DI):

Diabetes Insipitus (DI) DI is usually insidious but can occur with damage to the hypothalamus or the pituitary. ( neurogenic DI ) May be a result of defect in renal tubules, do not respond to ADH ( nephrogenic DI ) Decreased production or release of ADH results in massive water loss Leads to hypovolemic & dehydration.